Cholesterol accumulation in J774 macrophages induced by triglyceride-rich lipoproteins. Comparison of very low density lipoprotein from subjects with type III, IV, and V hyperlipoproteinemias.

Huff, Murray W.; Evans, Andrew; Sawyez, Cynthia G.; Wolfe, Benjamin; Nestel, P.J.

doi:10.1161/01.atv.11.2.221

Cited by 70 publications

(55 citation statements)

References 67 publications

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“…Endocytosed lipoproteins are delivered to lysosomes where their proteins and glycerides are hydrolyzed, thereby releasing fatty acids and other degradation products into the cytoplasm where they are available for further metabolism. Macrophages, however, endocytose few large, triglyceride-rich lipoproteins unless they have been partially metabolized (7,8). The second pathway involves extracellular hydrolysis of glycerides in lipoproteins, which allows the uptake primarily of the released free fatty acids (9), and is the major pathway responsible for fatty acid assimilation by adipocytes and myocytes (10).…”

Section: Introductionmentioning

confidence: 99%

“…1 Macrophages, unlike other phagocytic leukocytes (e.g., neutrophils, eosinophils, basophils), have evolved a method to obtain fatty acids without ingestion of whole lipoproteins. Macrophages secrete LPL (8,9), the major enzyme responsible for extracellular release of fatty acids from triglyceride-rich 1. Abbreviations used in this paper: 2-DG, 2-deoxy-d -glucose; CrP, creatine phosphate; DFBS, dialyzed fetal bovine serum; DiI-AcLDL, 11 Ј -dioctadecyl-3,3,3 Ј ,3 Ј -tetramethylindidocarbocyanine perchlorate acetyl LDL; E(IgG), IgG-opsonized sheep erythrocytes; 125 I-ox LDL, 125 I-labeled oxidized LDL; KO, knockout; L0-MCK, LPL knockout mice whose macrophages make no LPL; LPL, lipoprotein lipase; MCK, muscle creatine kinase; RBC, red blood cells; RT, reverse transcription; THL, tetrahydrolipstatin.…”

Section: Introductionmentioning

confidence: 99%

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Lipoprotein lipase regulates Fc receptor-mediated phagocytosis by macrophages maintained in glucose-deficient medium.

Yin¹,

Loike²,

Kako³

et al. 1997

J. Clin. Invest.

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During periods of intense activity such as phagocytosis, macrophages are thought to derive most of their energy from glucose metabolism under both aerobic and anaerobic conditions. To determine whether fatty acids released from lipoproteins by macrophage lipoprotein lipase (LPL) could substitute for glucose as a source of energy for phagocytosis, we cultured peritoneal macrophages from normal and LPL knockout (LPL-KO) mice that had been rescued from neonatal demise by expression of human LPL via the muscle creatine kinase promoter. Normal and LPL-KO macrophages were cultured in medium containing normal (5 mM) or low (1 mM) glucose, and were tested for their capacity to phagocytose IgG-opsonized sheep erythrocytes. LPL-KO macrophages maintained in 1 and 5 mM glucose phagocytosed 67 and 79% fewer IgG-opsonized erythrocytes, respectively, than macrophages from normal mice. Addition of VLDL to LPL-expressing macrophages maintained in 1 mM glucose enhanced the macrophages' phagocytosis of IgGopsonized erythrocytes, but did not stimulate phagocytosis by LPL-KO macrophages. Inhibition of secreted LPL with a monoclonal anti-LPL antibody or with tetrahydrolipstatin blocked the ability of VLDL to enhance phagocytosis by LPL-expressing macrophages maintained in 1 mM glucose. Addition of oleic acid significantly enhanced phagocytosis by both LPL-expressing and LPL-KO macrophages maintained in 1 mM glucose. Moreover, oleic acid stimulated phagocytosis in cells cultured in non-glucose-containing medium, and increased the intracellular stores of creatine phosphate. Inhibition of oxidative phosphorylation, but not of glycolysis, blocked the capacity of oleic acid to stimulate phagocytosis. Receptor-mediated endocytosis of acetyl LDL by macrophages from LPL-expressing and LPL-KO mice was similar whether the cells were maintained in 5 or 1 mM glucose, and was not augmented by VLDL. We postulate that fatty acids derived from macrophage LPL-catalyzed hydrolysis of triglycerides and phospholipids provide energy for macrophages in areas that have limited amounts of ambient glucose, and during periods of intense metabolic activity. ( J. Clin. Invest. 1997. 100:649-657.)

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lipoprotein lipase regulates Fc receptor-mediated phagocytosis by macrophages maintained in glucose-deficient medium.

Yin¹,

Loike²,

Kako³

et al. 1997

J. Clin. Invest.

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“…TGs in fasting plasma are carried in VLDLs, and these VLDLs have been found within human and experimental atherosclerotic lesions (3,4), providing a rationale to study their direct effects on macrophage functions such as foam cell formation and inflammation. It is well established that VLDL causes the accumulation of TGs and FFAs in macrophages (5)(6)(7)(8)(9). This can occur through three different mechanisms: 1) uptake of intact VLDL particles; 2) uptake of VLDL remnants resulting from lipoprotein lipase-mediated lipolysis; and 3) uptake of FFAs produced by VLDL lipolysis, which can be taken into cells through both passive diffusion and receptor-mediated mechanisms.…”

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confidence: 99%

The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages

Saraswathi

Hasty

2006

Journal of Lipid Research

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Hypertriglyceridemia is an important risk factor for atherosclerosis, especially in obesity. Macrophages are one of the primary cell types involved in atherogenesis and are thought to contribute to lesion formation through both lipid accumulation and proinflammatory gene expression. In this study, we sought to determine the direct impact of triglyceride (TG)-rich VLDL-induced lipid accumulation on macrophage proinflammatory processes. Incubation of mouse peritoneal macrophages with 100 mg/ml VLDL for 6 h led to 2.8-and 3.7-fold increases in intracellular TGs and FFAs, respectively (P , 0.05). The inflammatory proteins tumor necrosis factor-a, interleukin-1b, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, matrix metalloproteinase 3 (MMP3), and macrophage inflammatory protein1a (MIP-1a) were all upregulated by at least 2-fold (P , 0.05) in a dose-dependent manner in VLDL-treated macrophages. The increase in inflammatory gene expression coincided with the phosphorylation of the mitogen-activated protein kinase (MAPK) pathway members extracellular signal-regulated kinase (ERK) 1/2, stress-activated protein kinase/c-Jun NH2-terminal kinase, and p38 MAPK and was ameliorated by U0126, an inhibitor of ERK1/2. Inhibition of extracellular TG hydrolysis with tetrahydrolipstatin (Orlistat) resulted in the absence of intracellular TG and FFA accumulation and was accompanied by the amelioration of ERK1/2 phosphorylation and MIP-1a gene expression. These data indicate that VLDL hydrolysis, and the subsequent accumulation of intracellular FFAs and TGs, plays a substantive role in mediating the proinflammatory effects of VLDL. These data have important implications for the direct proatherogenic effects of VLDL on macrophage-driven atherosclerosis.-Saraswathi, V., and A. H. Hasty. Traditionally, LDLs have been thought to be the key plasma lipoproteins involved in atherosclerotic lesion development. However, with the dramatic increase in the prevalence of obesity around the world, associated lipoprotein abnormalities such as hypertriglyceridemia have been brought into focus. In fact, hypertriglyceridemia is now regarded as one of the main contributing factors to the development of atherosclerotic disease (1, 2), although the exact mechanisms by which triglycerides (TGs) function in atherogenesis are unknown. TGs in fasting plasma are carried in VLDLs, and these VLDLs have been found within human and experimental atherosclerotic lesions (3, 4), providing a rationale to study their direct effects on macrophage functions such as foam cell formation and inflammation. It is well established that VLDL causes the accumulation of TGs and FFAs in macrophages (5-9). This can occur through three different mechanisms: 1) uptake of intact VLDL particles; 2) uptake of VLDL remnants resulting from lipoprotein lipase-mediated lipolysis; and 3) uptake of FFAs produced by VLDL lipolysis, which can be taken into cells through both passive diffusion and receptor-mediated mechanisms. Despite these known pathways of mac...

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“…There is increasing evidence from cell culture studies in vitro 8,9 and human studies in vivo 10 -15 that postprandial, triglyceride-rich, apoB-containing lipoproteins are atherogenic. Furthermore, these postprandial lipoproteins may be more closely related to atherogenic risk than those lipoproteins in the fasting state.…”

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confidence: 99%

The HMG-CoA Reductase Inhibitor Atorvastatin Increases the Fractional Clearance Rate of Postprandial Triglyceride-Rich Lipoproteins in Miniature Pigs

Burnett

Barrett

Vicini

et al. 1998

ATVB

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Abstract-We have previously shown in vivo that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin decreases hepatic apolipoprotein B (apoB) secretion into plasma. To test the hypothesis that atorvastatin modulates exogenous triglyceride-rich lipoprotein (TRL) metabolism in vivo, an oral fat load (2 g fat/kg body wt) containing retinol (50 000 IU) was given to 6 control miniature pigs and to 6 animals after 28 days of treatment with atorvastatin 3 mg ⅐ kg Ϫ1 ⅐ d Ϫ1. A multicompartmental model was developed by use of SAAM II and kinetic analysis performed on the plasma retinyl palmitate (RP) data. Peak TRL (dϽ1.006 g/mL; S f Ͼ20) triglyceride concentrations were decreased 29% by atorvastatin, and the time to achieve this peak was delayed (5.2 versus 2.3 hours; PϽ0.01). The TRL triglyceride 0-to 12-hour area under the curve was decreased by 24%. In contrast, atorvastatin treatment had no effect on peak TRL RP concentrations, time to peak, or its rate of appearance into plasma; however, the TRL RP 0-to 12-hour area under the curve was decreased by 20%. Analysis of the RP kinetic parameters revealed that the TRL fractional clearance rate was increased significantly, 1.4-fold (3.093 versus 2.276 pools/h; Pϭ0.012), with atorvastatin treatment. The percent conversion of TRL RP from the rapid-turnover to the slow-turnover compartment was decreased by 47% with atorvastatin treatment. The TRL RP fractional clearance rate was negatively correlated with very low density lipoprotein apoB production rate measured in the fasting state (rϭϪ0.49). Thus, although atorvastatin had no effect on intestinal TRL assembly and secretion, plasma TRL clearance was significantly increased, an effect that may relate to a decreased competition for removal processes by hepatic very low density lipoprotein.

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Cholesterol accumulation in J774 macrophages induced by triglyceride-rich lipoproteins. Comparison of very low density lipoprotein from subjects with type III, IV, and V hyperlipoproteinemias.

Cited by 70 publications

References 67 publications

Lipoprotein lipase regulates Fc receptor-mediated phagocytosis by macrophages maintained in glucose-deficient medium.

Lipoprotein lipase regulates Fc receptor-mediated phagocytosis by macrophages maintained in glucose-deficient medium.

The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages

The HMG-CoA Reductase Inhibitor Atorvastatin Increases the Fractional Clearance Rate of Postprandial Triglyceride-Rich Lipoproteins in Miniature Pigs

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